Human cancer-prone genetic diseases are being studied in order to identify groups of people with an increased susceptibility to environmental carcinogenesis. We are attempting to discover the clinical consequences as well as the molecular basis of their cellular hypersensitivity. Patients with xeroderma pigmentosum (XP) and ataxia telangiectasia (AT), diseases with ultraviolet (UV) and X-ray hypersensitivity, respectively, and with the dysplastic nevus syndrome of hereditary cutaneous melanoma (DNS) are being studied. Detailed examinations of the clinical features of affected individuals are being made. A large retrospective XP literature study (more than 700 cases) and a prospective registry of XP patients is underway. Field studies in Israel detected a possible new form of XP with defective DNA repair without neoplasia. Clinical diagnostic features of DNS are being refined. Testicular abnormalities in AT are under study. Cultures of skin and blood from XP, AT and DNS family members were established. Effects on cell survival, mutagenesis, DNA synthesis and repair, histone synthesis and chromosome integrity after treatment with DNA damaging agents are being studied. DNS lymphoblastoid cell lines were found to be UV-hypermutable thus implicating DNS as a second hypermutable human disease (XP was the first recognized). We are using DNA mediated gene transfer to attempt to clone the genes responsible for UV hypersensitivity in XP cells. We have identified an XP cell line that is a highly proficient recipient of cloned genes. These studies may afford a means of detecting individuals with increased genetic risk of neoplasia and suggest modes of cancer prevention.